Modulation of apoptosis by cigarette smoke and cancer chemopreventive agents in the respiratory tract of rats

F. D'Agostini et al., Modulation of apoptosis by cigarette smoke and cancer chemopreventive agents in the respiratory tract of rats, CARCINOGENE, 22(3), 2001, pp. 375-380
Citations number
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ISSN journal
0143-3334 → ACNP
Year of publication
375 - 380
SICI code
Preclinical studies may elucidate the meaning of biomarkers applicable to e pidemiologic studies and to clinical trials for cancer prevention. No study has explored so far the effect of cigarette smoke on apoptosis in vivo. We evaluated modulation of apoptosis in cells of the respiratory tract of smo ke-exposed Sprague-Dawley rats both by morphological analysis and TUNEL met hod. In a first study, exposure of rats to mainstream cigarette smoke for e ither 18 or 100 consecutive days produced a significant and time-dependent increase in the proportion of apoptotic cells in the bronchial and bronchio lar epithelium. Oral N-acetylcysteine did not affect the background frequen cy of apoptosis but significantly and sharply decreased smoke-induced apopt osis, In a second study, exposure of rats to a mixture of sidestream and ma instream smoke for 28 consecutive days resulted in a >10-fold increase in t he frequency of pulmonary alveolar macrophages undergoing apoptosis, Dietar y administration of either 5,6-benzoflavone, 1,2-dithiole-3-thione or oltip raz did not affect the frequency of smoke-induced apoptosis, whereas phenet hyl isothiocyanate produced a further significant enhancement. Again, N-ace tylcysteine and its combination with oltipraz significantly decreased smoke -induced apoptosis, In both studies exposure to smoke resulted in a sharp i ncrease of cells positive for proliferating cell nuclear antigen (PCNA), wh ich was unaffected by the examined chemopreventive agents, These findings h ighlight the concept that modulation of apoptosis has diversified meanings. Different meanings (as explained in the following lines). First, the apopt otic process is triggered as a defense system against genotoxic agents, suc h as the components of cigarette smoke. The further induction produced by p henethyl isothiocyanate, favoring removal of damaged cells, represents an e xample of a detoxification mechanism. Inhibition of smoke-induced apoptosis by N-acetylcysteine should be interpreted as an epiphenomenon of antigenot oxic mechanisms, as shown in parallel studies evaluating modulation of DNA alterations in the respiratory tract of the same animals. Thus, it is impor tant to discriminate between whether the opposite modulation of apoptosis i s per se a protective mechanism or the beneficial outcome of other mechanis ms inhibiting genotoxicity.